Iingxaki ze-mesolimbic dopamine i-neurotransmission kwi-rat yokutya okunamafutha (2009)

Amagqabantshintshi: isifundo sityhila ukuba kukutya kakhulu "ukutya okutyela" ekutyebeni kakhulu kukhokelela ekunciphiseni kwamanqanaba e-dopamine kunye nokuphendula okungafunekiyo kwe-dopamine kwiigundane eziqhelekileyo. Nangona kunjalo, iigundane zazisenempendulo yomvuzo kukutya okutyela. Olunye lwezifundo ezininzi lubonisa utshintsho lobuchopho olufana nolo lukhoboka leziyobisi. Ngaphezulu kokusebenzisa iinguqulelo ezingaphaya kwembuyekezo yendalo kunokukhokelela ekubeni likhoboka.

Neuroscience. I-2009 Aprili 10; 159 (4): 1193-9. doi: 10.1016 / j.neuroscience.2009.02.007. Epub 2009 Feb 11.

BM Geiger,a M. Haburcak,a NM Avena,b,c U-Moyer we-MC,c BG Hoebel,c kwaye EN Pothosa,*

Inguqulelo yokugqibela yomhleli yeli nqaku iyafumaneka apha Neuroscience

Bona amanye amanqaku ku-PMC Wisdom nqaku epapashwe.

Yiya e:

Abstract

Ukonyusa umthamo we-caloric kukutya kakhulu kunokuqhutywa ziindlela eziphambili ezilawula indlela yokuziphatha efuna umvuzo. Inkqubo ye-dolamine ye-mesolimbic, kunye ne-nucleus ingqokelela ngokukodwa, iphantsi kokubini ukutya nomvuzo weziyobisi. Siphanda ukuba ingaba ukukhuluphala kokutya okunxulumana nokunxulunyaniswa notshintsho kwi-dopaminergic neurotransmission kuloo mmandla. I-Sprague-Dawley iigundane zabekwa kwindawo etyiwayo yokutya eklasini ukuze kunyanzelwe ukukhuluphala okanye ukutya kwelebhu ukuze kulondolozwe ubunzima obuqhelekileyo. Amanqanaba e-dopamine ye-extracellular yalinganiswa ngu kwi vivo Uhlalutyo oluncinci. Ukukhutshwa kwe-dopamine ekhutshwe ngombane kwakulinganiswa kwi-ex vivo kwizilayi ze-nucleus accumbens kunye ne-dorsal striatum isebenzisa i-real-time carbon fiber amperometry. Ngaphezulu kweeveki ezili-15, iigundane ezityiwayo ezityiwayo ziye zatyeba (> 20% yokunyuka kobunzima bomzimba) kwaye yabonisa amanqanaba asezantsi e-extracellular eqokelela amanqanaba e-dopamine kunamagundane obunzima obuqhelekileyo (0.007 ± 0.001 vs. 0.023 ± 0.002 pmol / isampuli; P<0.05). Ukukhutshwa kwe-Dopamine kwi-nucleus ye-accumbens yamagundane atyebileyo kwavuselelwa ngumceli mngeni wokutya, kodwa yahlala ingaphenduli kwisidlo sase-laboratory. Ulawulo lwe d-amphetamine (i-1.5 mg / kg ip) ikwatyhile impendulo ye-dopamine efunyenweyo kwiigundane ezi-feta. Uvavanyo olulinganisa ngombane olufakelwe kwi-dopamine umqondiso we-dopamine ex kwi-nuksi yokuqokelelwa kwe-nucleus lubonise impendulo ebuthathaka kakhulu kwizilwanyana ezityebileyo (12 vs. 25 × 106 Dopamine iimolekyuli ngokunyusa, P<0.05). Iziphumo zibonisa ukuba ukusilela kwi-mesolimbic dopamine neurotransmission kudityaniswa nokutya kakhulu. Ukudakumba koxinzelelo lwe-dopamine kunokukhokelela kwizilwanyana ezityebileyo ukuba zibuyekeze ngokutya ukutya okuthandekayo "kokuthuthuzela", isikhuthazi esikhuphe i-dopamine xa ilabhoratri ye-chow isilele.

Internet: I-nucleus accumbens, i-striatum, ukondla, ubunzima bomzimba, amphetamine, hyperphagia

Ukunyuka okuthe kratya kokutya okutyebileyo kwiindawo ezihambileyo zorhwebo kubonisa ukuba iindlela ezingezozamakhaya ezibonisa iindlela ezifanelekileyo zokufumana amandla anokusebenza. Umbuzo obalulekileyo kukuba kutheni izilwanyana zaselebhu kunye nabantu beqhubeka nokutya ukutya okune-enethiwekhi, enika amandla ukuya kwinqanaba lokuba batyebe. Ukusuka kwimbono yokuzivelela kwezinto, kuya kulindeleka ukuba ingqondo iphuhlise inkqubo yokuphendula kwimivuzo yendalo, njengokutya. Ezi ndlela ziphakathi zigcinwa kuzo zonke iintlobo zezilwanyana ukuze ziqiniseke ukusinda (IKelley kunye neBerridge, 2002) kwaye inokunxibelelana okanye ukuguqula ukujikeleza okulawula ubunzima bomzimba. Ke ngoko, ubukho bokutya okunencasa kunokubangela ukwanda kokutya kunye nokufumana ubunzima ukuba iindlela eziqhutywa likhaya, ezisuka ikakhulu kwi-hypothalamus, azinakoyiswa. Oku kunokuthi kuchaze, okungenani ngenxalenye, ubukhulu bokubhubhane kokutya kakhulu.

Okubalaseleyo phakathi kweenkqubo ze-neural ziindlela ze-mesolimbic dopamine, apho isenzo se-dopamine, ngakumbi kwii-termus ze-nucleus ze-nucleus, saziwa njengeendlela zokuqinisa. Ukuvulwa kwale nkqubo kubandakanya ukuphakama kwamanqanaba e-dopamine kunye notshintsho ekuguqukeni kwe-dopamine emva kokuziphatha okunomvuzo kwendalo njengokutya (UHernandez kunye noHoebel, 1988; URadhakishun et al., 1988). Ukongeza, i-dopamine kwi-nucleus accumbens (kunye ne-drial drial striatum eyaziwayo) iyaziwa ngokwanda ngokuchazwa kukhuthazo olunxulumene nokutya kunye nomsebenzi we-motor onxulumene nokufumaneka kokutya (I-Mogenson kunye ne-Wu, i-1982; Bradberry et al., 1991; Salamone et al., 1991). Yiyo loo nto kusengqiqweni ukulindela ukuba ukutyeba kakhulu ngokutya kunganxulunyaniswa namandla okukhupha i-mesolimbic dopamine.

Kolu phando, siphande ukuba ingaba ukuvezwa okungapheliyo (iiveki ze-15) zamagundane kukutya okunamandla, ukutya okutyayo kweklasikhi kubangela utshintsho kwi-dutamine ye-nusus. Oku kutya kuthandeka kakhulu kuyaphumelela ekuphembeleleni ukutyeba kakhulu kwizidalwa kwaye kufaneleke kakhulu kuphuhliso lokutyeba kakhulu komntu (Sclafani kunye Springer, 1976). Ngaphaya koko, ukutya okutyelwa nge-cafeteria kusivumele ukuba sahlule phakathi kokukhetha okunamafutha aphezulu kunye ne-carbohydrate eninzi kwaye nokuba olo khetho luchaphazele ukukhutshwa kwe-mesolimbic dopamine. Sifumanise ukuba iigundane ze-Sprague-Dawley zithathe uninzi lwazo lwe-caloric yokutya kwimithombo ephezulu ye-carbohydrate kwaye ziphuhlise ukukhuluphala okubangelwa kukutya (DIO). Ngapha koko, babonisa ukudakumba okukhuselekileyo kwe-basal dopamine kwi-nucleus accumbens kunye nempendulo ye-dopamine efunyenwe kwisidlo esisezingeni eliphantsi okanye ulawulo lwenkqubo d-mamphetamine.

IINKQUBO ZEMISEBENZI

izilwanyana

Iialbhino zababhinqileyo ababhinqileyo i-Sprague-Dawley (Taconic, Hudson, NY, USA), zathathelwa ubunzima bomzimba we-300 g nganye eneminyaka eyi-3 yeenyanga. Kwakhethwa izilwanyana kuba, ngokuchasene neempuku zamadoda, ubungakanani bomzimba wabasetyhini abasebenza elabhoratri buzinzile ngokuhamba kwexesha. Izilwanyana zahlaliswa ngokukodwa kwigumbi elinye phantsi komjikelo we-12-h reverse ukukhanya / umnyama (izibane kwi: 6 pm, izibane zicimile: 6 am). Ngaphantsi kwezi meko asikhange sibonane mpembelelo kwisigaba somjikelezo we-estrous on mesolimbic dopamine release (I-Geiger et al., 2008). Zonke izilwanyana zasetyenziswa ngokuhambelana nezikhokelo ezipapashiweyo ze-US National Institutes of Health (NIH) kunye ne-Institutional Animal Care and Committee Committee (IACUC) yeYunivesithi yaseTufts kunye neZiko Lonyango laseTufts. Yonke imizamo yenziwa ukunciphisa inani lezilwanyana ezisetyenziselwa ukunciphisa ukusetyenziswa kwezilwanyana kunye nokubandezeleka.

Ukwenziwa kwecafeteria

Izilwanyana zahlulwa kwiqela le-DIO yecafeteria (ikwachazwa njengeqela lokutya le -eseji engezantsi) kunye neqela elebhu elenzelwe utywala (iqela lesisindo eliqhelekileyo). Onke amaqela ayondliwa ad adum. Ukutya kwecafeteria kubandakanya izinto ezinamafutha aphezulu anjengeCrisco (33% ukuncitshiswa kwemifuno, i-67% iPurina powder), isalami, itshizi yecheddar kunye nebhotolo yamandongomane; kunye ne-carbohydrate ephezulu enje ngobisi oluphuculweyo (uphawu lweMagnolia exutywe namanzi, i-1: i-1), iicokitshi zetshokholethi, itshokholethi yobisi, iibhanana, i-marshmallows kunye nesisombululo se-32%. Oku kutya kuthandeka kakhulu kuboniswe ukuba kusebenza kakhulu ekuphembeleleni ukutyeba okutya kakhulu kwiigundane kunye nokulinganisa uphuhliso lokutyeba kakhulu komntu (Sclafani kunye Springer, 1976). Inxalenye nganye yezi zinto yayifumaneka ngalo lonke ixesha kwaye itshintshe amaxesha amane ngeveki. Iqela lendawo yokudlela yaseDio, ukongeza kokutya okunokutya, nako kwanikwa ad adum ukufikelela kwiPurina elebhu yelebhu. Ukuchonga ukhetho olukhethiweyo lokutya, ukuthathwa kwenxalenye nganye yesidlo sokutya kwekhitha kulinganiswe ngaphezulu kwamaxesha amabini e-48-h ngexesha leveki yeshumi elinanye yokutya. Ubunzima bomzimba babhalwa kanye ngeveki.

Utyando lwe-stereotaxic

Unyango lwe-Stereotaxic lwenziwa ngeveki 7 yesifundo (n= I-24 yokudlela ye-Dio amagundane, n= I-32 yeelebhu yeelebhu chow). Izilwanyana zazingafakwanga i-ketamine (60 mg / kg ip) kunye ne-xylazine (10 mg / kg ip) yokufakwa kwi-bilateral 10 mm, 21 gauge stainless-iron Microbalal Isikhokelo se-cannulas ejolise kwimimandla engasemva ye-nucleus accumbens ingingqi yeqokobhe. Abaququzeleli be-stereotaxic baba yi-10 mm ingaphandle kwangaphakathi zero, i-1.2 mm emva kwexesha kwi-sinsagittal sinus kunye ne-4 mm ventral ukuya kwinqanaba lomphezulu. I-fiber yokucofa dialysis yongeze enye i-4 mm ventral ukufikelela kwindawo ekujoliswe kuyo (I-Paxinos ne-Watson, i-2007). Emva kotyando, zonke izilwanyana zabuyiselwa kwiikati zazo zaza zaqhubeka nerejimeni yazo yokutya.

I-Microdialysis kunye nokusebenza okuphezulu kwe-chromatography yolwelo ngokubona kwe-electrochemical (HPLC-EC)

I-Microdialysis yenziwa ngeveki 14 yesifundo ukuvumela ukululama okwaneleyo kotyando. Kwiseshoni nganye ye-Microphyalysis izilwanyana zabekwa ngokwahlukeneyo kwimibhobho yokuhlola isifo kunye ne-probes yabekwa kwi-Microsalal cannulas 12-15 h ngaphambi kokuqokelelwa kwesampula yokuqala. Indawo yokufakelwa (ngasekhohlo kunye nasekunene) yayinxamnye nomhlaba. I-Microdialysis probes yayizizohlobo lokugxininisa, zenziwe ekuhlaleni kwaye zibonise ukubuyiswa kwe-10% ye-neurochemicals kwi in vitro iimvavanyo njengoko zichaziwe ngaphambili (Hernandez et al., 1986). Iiprosesa zagqitywa ngesisombululo seRinger (142 mM NaCl, 3.9 mM KCl, 1.2 mM CaCl2, 1.0 mM MgCl2, 1.4 mM Na2HPO4, 0.3 mM NaN2PO4) ngereyithi ye-1 ° µl / imiz. Iidayalate yayiqokelelwa kwi-40 vil vials equkethe i-5 µl yolondolozo (i-0.1 M HCl kunye ne-100 ° µM i-EDTA) ukucothisa i-oxidation ye-monoamines. Ukuqokelelwa kweesampulu kwaqala kumbindi womjikelo wobumnyama, kwaye konke ukutya kwasuswa nge3 h ngaphambi kokuba kwenziwe isampulu yazo zonke izilwanyana. Iisampulu zaqokelelwa kwizithuba ze-30-min ubuncinci kwi-2 h yesiseko, kwaza kwalandelwa ngenaliti yenqubo d-amphetamine (1.5 mg / kg ip; Sigma, iSt. Louis, MO, USA). Ukusuka kwisampulu nganye, i-25 µl ye-dialysate yafakwa kwi-amperometric Antec HPLC-EC system (GBC, Inc., Boston, MA, USA) ikholam ye-10 cm ye-rainin kunye ne-buffer yesigaba se-phosphate esahlula kwaye yabona i-dopamine, kwaye i-dopamine metabolites dihydroxyphenylacetic acid (DOPAC) kunye ne-homovanillic acid (HVA). Izikhonkwane eziziphumo zaye zalinganiswa zarekhodwa. Ukubekwa kwengqina ye-micodialysis kwindawo ekujoliswe kuyo yaqinisekiswa ekugqibeleni kovavanyo ngovavanyo lwe-histological lwephecana lokuhlola emva kokulungiswa kwengqondo nge-paraformaldehyde.

Kwizilwanyana ezibonakaliswe i-30-min ilabhoratri ye-chow okanye ucelomngeni wokutya endaweni yokutya d-amphetamine, onke amaqela ayevinjelwe ukutya nge-12 h ngaphambi kovavanyo lwe-Microphyalal ukuqinisekisa ukhuthazo olululo lokutya.

Isilayi electrophysiology

Iingqondo zerat zibekwe ngokukhawuleza kwi-oksijini ebandayo ye-oksijini ye-oksijini ye-oksijini (aCSF) kwi-leica VT1000S vibratome (Leica Microsystems, Wetzlar, Germany), kwaye yasikwa kwii-300 µm coronal clices. Igumbi lokuhlambela eliqulathe i-aCSF (124 mM NaCl, 2.0 mM KCl, 1.25 mM KH2PO4, 2.0 mM MgSO4, I-25 mM NaHCO3, 1.0 mM CaCl2, I-glucose ye-11 mM, pH = 7.3). Emva kwe-1 h kwizikhuhli ze-aCSF zatshintshelwa kwigumbi lokurekhoda ngesiqhumiso se-oksijini i-aCSF isethwe kwi-1 ml / min kwi-37 ° C. I-electrodes ze-Carbon fiber, i-5 µm ubukhulu, kunye nendawo entsha esikiweyo yabekwa kwi-nucleus accumbens igobolondo okanye i-dorsal striatum ~ 50 µm kwisisele, kunye ne-reference electrode (i-Ag / AgCl wire) ifakwe kwi-aCSF yokuhlambela kunye neseti yevolthi ukuba + i700 mV (Axopatch 200 B, Axon Izixhobo Inc., Union City, CA, USA). I-bipolar, i-wire ejijekileyo, i-electrode evuselelayo (isentimitha ye-0.005 kwi: MS 303 / 3, Plastics One, Inc., Roanoke, VA, USA) ibekwe ngaphakathi kwe-100-200 µm ye-carbon fiber electrode. Isikhuthazo esiqhubekayo sangoku se-monophasic yangoku ye-2 ms kwi + 500 µA ihanjiswe nge-Isoflex stimulus isolator (AMPI, Inc., iJerusalem, i-Israel) ibangelwa ngumvuseleli oqhubekayo-wangoku (Model S88; Grass Technologies, West Warwick, RI, USA) . Impendulo ye-electrode ye-amperometric (utshintsho kwisiseko) ibekwe iliso kwaye yacaciswa sisoftware yeSuperscope (GW Equipment, Inc., Somerville, MA, USA). I-Electrodes ibilungisiwe ngaphambili nangemva kokusetyenziswa kwe-voltammograms engasuswanga ((amaza amahlanu asetyenzisiwe kwaye avareji, i-300 V / s, −400 ukuya + 1000 mV, ekurekhodeni phakathi naphakathi nge-10 µM ​​dopamine). Iziqwengana ze-Amperometric zachongwa njengeziganeko ezinkulu kune-3.5 × ingxolo ye-rms yesiseko. Ububanzi besiganeko yayilixesha eliphakathi koku (a) isiseko sokungena kwisilinganiselo esilinganiselweyo ukusuka kwisiseko ukuya kwindawo yokuqala esedlula ukusika kunye (b) nenqaku ledatha yokuqala emva kokuphakama okukhulu okubhalise ixabiso le-≤0 pA. Ubuninzi beplanethi (imax) yomsitho yayiyeyona nto iphezulu Ukuchonga inani lilonke le molekyuli (N) ekhutshiweyo, iyonke intlawulo yomsitho phakathi konxibelelwano olusisiseko yagqitywa, kunye nenani le molekyuli eqikelelwa kulwalamano N= Q /nF, iphi intlawulo, n Inani leelektroni ezinikezelwe ngemolekyulu nganye, kwaye uF uhlala engowe-Faraday (96,485 C ngokulinganayo). Uqikelelo lwalusekwe ekucingeleni ii-elektroni ezimbini ezinikeziweyo ngemolekyuli enye ye-dopamine (I-Ciolkowski et al., 1994).

Iibhanti microsunches

Icafeteria DIO okanye iilebhu zelebhu eziselabhoratri (n= I-11 / iqela) zakhutshwa njengasekuvavanyweni kwangaphambilini kunye ne-1 mm kukwehliswa kwe-dorsal striatum kunye ne-nucleus accumbens kwathathwa kwii-300 µm izingcezu zobuchopho. Iipunchs zaye zavezwa kwisisombululo se-40 mM KCl ye-3 min ukukhuthaza ukukhutshwa kwe-dopamine. Amanqanaba e-dopamine ye-extracellular ke ayalinganiswa kusetyenziswa indlela ye-HPLC echazwe apha ngasentla.

Uhlalutyo lwedatha

Iindlela ezimbini ze-ANOVA (iqela lexesha le-x) kunye namanyathelo okuphindaphindiweyo kunye nohlalutyo lwe-hoc post njengoko kufanelekile lwalusetyenziselwa ukuhlalutya kwedatha ye-Microdialysis. I-ANOVA yendlela enye yayisetyenziselwe lonke olunye uvavanyo. Kwizilingo zesilayidi, iziphumo ezivela ezintlanu zokuphakanyiswa ezahlukeneyo kwisilayi esinye zaphindaphindwa kwisilayi esinye ngaphambi kokuqhutywa kwe-ANOVA. Iziphumo zibonakalisiwe njengempazamo yomgangatho error wempazamo (SEM).

IINKCUKACHA

Iigundane ezityiwayo zokutya zinokuthanda okona kutya kuthandwayo kakhulu

Iigundane zeCafeteria DIO zibonise ukuthanda okomelele kubisi olunencasa (74.4 ± 6.4 g; 241 ± 21 kcal) kunye nesisombululo se-32% scrose (31.4 ± 4.1 g; 40 ± 5 kcal) (Umzekeliso. 1A, B, F(9,127) = 116.9854, P<0.01). Ukongeza, ezi zilwanyana zitye kakhulu i-Purina chow (5.66 ± 1.02 g) ngokuthelekiswa nezilwanyana zaselabhoratri ezityisiweyo (54.7 ± 2.3 g; F(1,27) = 419.681, P<0.01). Emva kweeveki ezili-14 kwisidlo sokutya, iigundane zafumana i-53.7% yesisindo sokuqala somzimba kubunzima bokugqibela be-444.9 ± 19.0 g. Emva kwexesha elifanayo, iigundane kwi-chow yelebhu zafikelela kubunzima bokugqibela be-344.0 ± 10.8 (Umzobo 2A).

Ikhiwane. 1 

Icandelo lokondla ukutya kwecafeteria kwiigundane ezi-feta. Ukusetyenziswa okuphakathi kwezinto zokutya ze-cafeteria kwiigradi (A) kunye ne-kcal (B) ngaphezulu kwexesha ezimbini ze-48-h phakathi evekini 11 yendlela yokutya ebonakalayo ikhetha ukuthanda ubisi olunencasa kunye nesisombululo se-sucrose (kuthetha ± SEM; ...
Ikhiwane. 2 

Isiseko, i-amphetamine- kunye neelabhoratri yokutya ephikisayo inselelo yokufumana inqanaba le-dopamine iyancipha kwizidudu ze -eseji yokutya. (A) Ubunzima bomzimba wegreyadi ye-DIO ngexesha leveki ye-14-yeyona nto ibhetele kakhulu kuneyona ilabhoratri ye-elebhu ...

Iigundane ezityiweyo zokutya zine-dopamine ephantsi kwaye kuncitshiswe ukukhutshwa kwe-amphetamine

Ngeveki i-14 yesifundo, iigundane ze-Dio ze-ceteratia zibonisa amanqanaba asezantsi e-dopamine asezantsi kwi-nucleuseba, xa kuthelekiswa neelebhu ze-lob-fed (i-0.007 ± 0.001 pmols / 25 µL isampulu; 0.023 ± 0.002 olsL samp; Umzobo 2B, F(1,19) = 11.205; P<0.01), njengoko kulinganiswe nge kwi vivo Ukuvavanywa kwentsholongwane. Amanqanaba osiseko we-dopamine metabolites, i-DOPAC ne-HVA, afunyanwe ukuba asezantsi kakhulu kwindawo yokutya iigundane ze-DIO. Amanqanaba e-DOPAC kwindawo yokutyela iigundane ze-DIO yayiyi-3.13 ± 0.42 vs. 8.53 ± 0.56 pmol kwi-laboratory ye-chow-fed rats (F(1,10) = 14.727, P<0.01). Amanqanaba e-HVA ayengu-1.0 ± 0.28 vs. 4.28 ± 0.33 pmol ngokwahlukeneyo (F(1,20) = 6.931, P<0.05). Emva kokusekwa kwesiseko esizinzileyo se-dopamine, iigundane zanikwa inaliti ye-1.5 mg / kg ip ye-amphetamine. Ukukhutshwa ngokupheleleyo kwamanqanaba e-dopamine ahlaziyiweyo ayengaphantsi kwindawo yokutya iigundane ze-DIO xa kuthelekiswa nezilwanyana zaselebhu ezondliweyo (Umzobo 2B, F(9,162) = 2.659, P<0.01).

Ukutya iigundane ezityiwayo kukhupha i-dopamine kwi-nucleus ye-nucleus xa itya ukutya okunencasa kakhulu, hayi elebhu yelebhu engenanto.

Umzobo 2D ibonisa ukuba amanqanaba e-dopamine ye-extracellular dafamine kwindawo yokutyela iigundane ze-DIO ayonyukanga ngendlela ebonakalayo ekuphenduleni isidlo seelebhu elebhu. Izilwanyana zitye kwi-1.3 eqhelekileyo ± 0.4 g ye-chow ngaphezulu kwe-30 min. Nangona kunjalo, xa i-subset yezi zilwanyana (n= 8) emva koko yondliwa isidlo sekhabhathi nge-30 min, i-dopamine inyuswe i-19.3% ukusuka kwi-0.027 ± 0.003 ukuya kwi-0.033 ± 0.004 pmols / 25 µL isampulu (F(11,187) = 8.757, P<0.05). Amanqanaba e-DOPAC nawo anyuke nge-17.13% ± 6.14%. Ngokwahlukileyo, amanqanaba e-dopamine kwilabhoratri yezilwanyana ezondliweyo ezonyuswe nge-51.10% ± 17.31% (F(7,119) = 3.902, P<0.05) 1 h emva kwesidlo se-chow (izilwanyana zitye kwi-avareji ye-5.7 ± 0.8 g, ngakumbi ngaphezulu kwezilwanyana ze-DIO; F(1,33) = 26.459, P<0.01). Nangona kunjalo, asilindelanga ukuba ukutya okusezantsi kwezilwanyana ze-DIO kungunobangela othe ngqo wokungabikho kokukhutshwa kwe-dopamine kwezi zilwanyana kuba ukutya ukutya okuncinci njenge-0.6 g kuye kwaxelwa ukuba kukhuthaze ukukhutshwa kwe-dopamine kwi-nucleus accumbens yeempuku (IMartel kunye neFantino, i-1996). Ngaphaya koko, olunye uphononongo lubonise ukuba umahluko kwixabiso le-dopamine ekhutshiweyo aludityaniswa ngqo kubungakanani bokutya okukhoyo, kodwa unokuchatshazelwa yenye imiba enje ngokwenqanaba lokutya kwesilwanyana, ubushushu kunye nemiphumo emibi yokutya okuboniswayo (Hoebel et al., 2007). Ukutya kwecafeteria akunikwanga njengomceli mngeni kwizilwanyana ezenziwa elebhu ngenxa yokuba kulindelwe ukuba kuvelise iziphumo ezinobuzaza ezinokuphambanisa nakuphi na ukuthelekisa izilwanyana zeDio.

Ukukhutshwa kweedopamine ngombane okukhuthazwayo kumacwecwe obuchopho asebusweni obuvela kwiigundane ezityayo zokutya

Umzobo 3A ibonisa abalinganiswa be-amperometric ukusuka kwi-nuksi eqokelela izilwanyana zegobolondo kwiigundane eziqhelekileyo zokutya kunye nokutya (n= Ukunyuswa kwe-30 kwizilonda ezisixhenxe ngokuchasene novuselelo lwe24 kwizilonda ezihlanu ngokulandelelana). Iigundane zeCafeteria DIO zazikhuphe ngaphandle kombane ukukhutshwa kwe-dopamine kunamagundane elebhu elebhu (12 × 106I-4 × 106 vs. 25 × 106I-6 × 106 iimolekyuli; Umzobo 3B, F(1,52) = 2.1428, P<0.05). Lo mahluko kukhutshwe ukukhutshwa kwe-dopamine kubonakalisa ukwehla kokuphakama komsitho (5.16 ± 1.10 pA kwindawo yokutyela iigundane ze-DIO vs. Umzobo 3C, F(1,52) = 2.4472, P<0.05) kunye nobubanzi (2.45 ± 0.73 s kwindawo yokutyela iigundane ze-DIO vs. Umzobo 3D, F(1,52) = 3.851, P<0.05).

Ikhiwane. 3 

Ukukhutshwa kwe-dopamine ekhutshiweyo kwi-nucleus accumbens kwizilumko zengqondo (A) Ukutsala okulandelwayo ukusuka kwi-coronal nucleus ye-ascelles izilwanyana zezilwanyana ezi-chow-feed (phezulu; n= Ukunyusa kwe-30 kwizilonda ezisixhenxe) nakwizilwanyana ze-Dio zethafile (ezantsi; n= I-24 inkuthazo ...

Ikhiwane. 4 ibonisa ukuba iimeko ezifanayo zazikho kwiziqwenga zamanqatha ezorhwebo zokutya zee-oese zokutya. Umnxibelelanisi wokumela ovela elebhu elebhu (n= Unyuselo lwe-31 kwizilonda ezisixhenxe) nakwindawo yokutyela yeDio (n= I-15 inkuthazo kwizicwili ezine) amaqela abonisiwe kwi Umzobo 4A. Ukukhutshelwa kwe-dopamine yombane kwi-striatum yayiyi-0.8 × 106I-0.1 × 106 Kwindawo yokutyela i-DIO rats vs 44 × 106I-11 × 106 iimolekyuli (Umzobo 4B, F(1,45) = 6.0546, P<0.01) kwilabhoratri yezilwanyana ezondliweyo. Kwakhona oku kubonisa ukwehla kokubaluleka kokuma komnyhadala (2.77 ± 0.42 vs. 9.20 ± 1.88 pA; F(1,45) = 7.8468, P<0.01) kunye nobubanzi (0.22 ± 0.03 vs. 5.90 ± 0.98 s; F(1,45) = 17.2823, P<= 0.01) kwiqela lokutyela le-DIO group (Umzekeliso. 4C, 4D).

Ikhiwane. 4 

Ukukhutshwa kwe-dopamine ekhutshiweyo kwi-dorsal striatum kwizilumko zobuchopho. (A) Ukulandelwa kokumelwa ukusuka kwizilonda ezinobunzima be-dorsal striatum yezilwanyana ezondisiweyo (ngaphezulu; n= Ukunyusa kwe-31 kwizilonda ezisixhenxe) nakwizilwanyana ze-Dio zethafile (ezantsi; n= I-15 inkuthazo ngaphakathi ...

Ukukhutshwa kwe-dopamine ye-potasium-ekhuthazwayo ye-micropunches ye-tishu kuncitshiswa kwii-nucleus accumbens kunye ne-striatum yamagundwane adliwe kukutya

Amanqanaba e-dopamine ye-extracellular emva kokunyuswa kwe-KCl ayalinganiswa yi-HPLC-EC kwaye aboniswe kuyo Ikhiwane. 5. Amanqanaba e-dopamine ye-extracellular dopamine yi-0.16 ± 0.08 pmol / isampulu kwii-micropunches zezilwanyana ezikhulupheleyo (n= I-10 micropunches) ngokuthelekiswa ne-0.65 ± 0.23 pmol / isampulu kwimikroskowudi evela kwizilwanyana ezilawulayo (n= I-micropunches ye-11; Umzobo 5A; F(1,19) = 4.1911, P<0.01). Amanqanaba e-dopamine angaphandle ayengu-5.9 ± 1.7 pmol / isampuli kwimicropunches ye-striatal evela kwi-obese (n= I-8 micropunches) iigundane kunye ne-11.3 ± 1.9 pmol / isampulu kwindawo enye ukusuka kulawulo (n= I-11 micropunches) iigundane (Umzobo 5B; F(1,17) = 7.5064, P<0.01).

Ikhiwane. 5 

Amanqanaba e-dopamine ye-extracellular ukusuka kumacropunches e-potasium-achukumisiweyo. Inani le-dopamine ekhutshwe kwi (A) i-nucleus accumbens (n= I-11 micropunches kwiqela ngalinye) kunye (B) ne-drial striatum (n= I-8 micropunches evela kwi-feta kunye n= I-11 micropunches ukusuka kulawulo) ...

UKUQALA

Kolu phononongo, iigundane ziba butyebile kukutya ukutya okune-cafeteria kukhethwa kukutya okune-carbohydrate ephezulu. Kwimeko yabo yokukhuluphala, babene-dopamine ephantsi esal extracellular dopamine kunye ne-chow-evuseleliweyo okanye i-amphetamine-ivuswe dopamine kwi-nucleus accumbens. Kwizifundo ezisebenzisa iziyobisi zokuxhatshazwa, izilwanyana ziya kusebenza ukugcina amanqanaba e-dopamine kwi-nucleus accumbens ngaphezulu kwenqanaba elithile (Ubulumko et al., 1995a,b; Ranaldi et al., 1999). Kwisifundo esikhoyo, "into" ehlukumezayo kukutya okunokutya, ngoko i-dopamine ephantsi ye-extracellular dermamine ekhokelela ekusetyenzisweni okwandayo kokutya okuthandekayo.

Iigundane ze-Obese zikwabonisa amanqanaba afunyenwe kwi-dopamine esebenza ngombane kwizilungiso zobuchopho kunye ne-potassium ekhuthazwayo ye-dopamine kwimicrosunches ye-tishu evela kwi-nucleus accumbens kunye ne-dorsal striatum. Intsilelo ephambili ye-presynaptic kwi-dopamine exocytosis, ke ngoko, ibonakala kukutya okunexhala kokutya kuba uxinzelelo lwedopamine ikhutshiwe kwi vivoKwizinto ezikwi-striatal striatal kunye nakwiziqwenga zobuchopho kunye nakwimicrosunches yezicubu ezivela kwizilwanyana ezityayo. Sibonile isiphumo esifanayo kwimodeli yemfuza yokutyeba kakhulu. Kule modeli, i-mRNA kunye nokuhanjiswa kweprotein kwabalawuli be-dopamine synthesis kunye ne-exocytosis kubandakanya i-tyrosine hydroxylase kunye ne-neuronal vesicular monoamine transporter (VMAT2) iyancitshiswa kwindawo ye-ventral tegmental area (VTA) dopamine neurons yezilwanyana ezithanda ukutyeba kakhulu (I-Geiger et al., 2008). Enye indawo enokubakho yinguqu yangaphambi kwexesha le-synaptic yiplma membrane dopamine yokuphinda iphindise ukuhambisa, i-DAT. Izifundo ze-electrophysiology zesilayidi zisivumela ukuba sahlule phakathi kokungafani kokukhutshwa kwe-dopamine ngokuchasene nokubuyisela kwakhona i-kinetics. Umahluko kububanzi be-spike ucebisa kumgaqo-nkqubo wokuba izidlo ezityebileyo zokutya izilwanyana zinokuba nazo kungekuphela nje ukukhutshwa kodwa zikwatshintsha ekubuyiseleni kwakhona ngenxa yokungafani kweendawo zokuhambisa ezisebenzayo ze-DAT kwisahlulo seplasma. Inamafutha eZucker (fa / fa) iigundane, ukunyuka kwe-mRNA amanqanaba e-DAT transporter kuxeliwe kwiVTA (I-Figlewicz et al., 1998). Amandla okunyuswa kokucocwa kwe-dopamine ahambelana nesibonakaliso esinciphile sokukhupha i-dopamine kwiirati ze-DIO kwisifundo esikhoyo.

Kuya kufuneka sazi ukuba amandla okukhupheleka kwe-amphetamine ayifakwanga kwizilwanyana ezirhubuluzayo (ngokweepesenti zotshintsho olusisiseko) kwaye oku kunokuba “nokucebisa” kunye namanqanaba asezantsi edopamine yokuqhubela phambili izilwanyana ezityebileyo ukuba zifumane ukukhululwa kwe-dopamine. I-Amphetamine sisiseko esibuthathaka esusa i-dopamine ukusuka kwi-vesicles ukuya kwi-cytosol kwaye ikhokelela ekunyuseni kwe-dopamine ye-extracellular ngothutho olubuyela umva (I-Sulzer kunye neRayport, 1990). Kwiimeko zokushokoxeka okukhulu kumadama e-dopamine vesicular, umzekelo kwimeko ye-veicular transporter ye-VMAT2 intsilelo, inaliti ye-amphetamine inyusa kancinci i-dopamine synthesis kwi-cytosol (Ifonti et al., 1997). I-amphetamine ebangelwa kukonyuka okwethutyana kwe-cytosolic dopamine inokuchaza ukwanda okwethutyana lweepesenti zotshintsho lwe-dopamine kwizilwanyana ezigqithileyo ngaphezulu koko kuqatshelwe kwizilwanyana eziqhelekileyo ezinobunzima kwaye inokuba negalelo kubuchwephesha bezilwanyana ezi-oese ukuba zikwazi ukuphinda zikhuphe ishukumo kunye nesezantsi amanqanaba e-dopamine kwii-accumbens.

Yeyiphi indlela enokuthi ibenamandla okulamula ukusilela kwempazamo ye-dopamine kwizilwanyana ezirhabaxa kunye nokuqhuba ukutya abazithandayo? Ikhonkco phakathi kokukhethwa kokutya kunye ne-nucleus accumbens dopamine iboniswe ngokucacileyo kwimpendulo egwenxa yokutya kwezilwanyana ezi-oese zokutya kwi-chow, kodwa hayi kukutya okuthandekayo. Iziphumo zethu zifezekisa umsebenzi wakutshanje obonisa ukuba i-dopamine D1-uhlobo receptor (D1) i-receptor agonist iphucule ukuthandwa kweempuku kukutya okuthandekayoUmSebenzi kunye neAl-Naser, 2006). Ukongeza, i-nucleus ibutha i-dopamine yenziwe yasebenza kwiigundane eziqeqeshelwe ukuziluma kwi-sucrose (Avena et al., 2008), ukuxhasa ngakumbi ukubandakanywa kwe-dopamine ephambili ekukhetheni ukutya okufumaneka ngokutya okutyebileyo kwi-carbohydrate. Sibonakalise intsilelo ephakathi ye-dopamine exeliweyo kwisifundo esikhoyo kwiimodeli ezongeziweyo zokutyeba, kubandakanya ob / ob Impazamo ye-leptin enesiphene kunye ne-inbred rate-proneUFulton et al., 2006; I-Geiger et al., 2008). Ke ngoko, uphawu olunye olunokunxibelelanisa ukusetyenziswa kokutya okufumanekayo kunye nokuqokelela ukukhutshwa kwe-dopamine kunokuba lptin. Kubantu abane-leptin enesifo sokuzalwa, ukutshintsha kwe-leptin kunciphisa i-hyperphagia yabo kwaye kutshintsha ukusebenza kwe-striatum yabo ye-ventral ngokubhekisele ekuboneni ukutya okunesondloI-Farooqi et al., 2007). Kwiigundane kubonisiwe ukuba i-leptin iyakucutha ukuzilawula kwe-sucrose (I-Figlewicz et al., 2006, 2007). Olunye ugalelo lwe-orexigenic njenge-ghrelin kunye ne-orexin lubonakalisiwe ukuba lubandakanyeke kusebenze kwenkqubo ye-midbrain dopamine (URada et al., 1998; IHelm al al., 2003; Abizaid et al., 2006; UNarita et al., 2006). Kuya kuba ngumdla ukuqhubeka ukujonga ukuba ingaba ukutshintshela izilwanyana ezitya ukutya endaweni yelebhu eqhelekileyo ngokuhlala kungagcina ukuthandwa kwazo kukutya okuqinisekileyo kunye ne-dessamine ye-dopamine ehambelana nayo ngokuzimeleyo kwiinguqu ezilindelekileyo kwi-leptin, ghrelin okanye i-orexin kunye nezinye iimpawu inxulumene nommiselo wokutya.

ISIPHELO

Ukuqukumbela, iziphumo zolu phononongo zibonisa ukuba inkqubo ye-dolamine ye-mesolimbic idlala indima ebalulekileyo ekukhetheni ukutya okunamandla, i-hyperphagia kunye nesiphumo sokutya kakhulu. I-nucleus accumbens kunye ne-dorsal striatum dopaminergic neurotransication zixinezelekile kwizidudu ze -eseji yokutya. Izilwanyana zinokubuyisela okwethutyana amanqanaba e-dopamine ngokutya okunencasa, ukutya okunamandla. Ezi ziphumo zicebisa ukuba ukukhetha ekujoliseni abalawuli abaphambili be-mesolimbic dopamine yenkqubo yokwenza into ethembekileyo yokunyanga ukukhuluphala ngokutya.

Imibulelo

Lo msebenzi uxhaswe yi-DK065872 (ENP), F31 DA023760 (BMG, ENP), imbasa ye-Smith Family Foundation yokuGqibela kuPhando lweBiomedical (ENP) kunye neP30 NS047243 (iZiko leTufts loPhando lweNeuroscience).

izifinyezo

  • I-aCSF
  • ulwelo olusebenzayo lwecypbrospinal
  • DAT
  • Dopamine iplasma membrane transporter
  • I-DIO
  • Ukutya okubangelwa kukutya kakhulu
  • I-DOPAC
  • I-dihydroxyphenylacetic acid
  • IHPLC-EC
  • ukusebenza kwe-chromatogra ephezulu yokusebenza ngokuchongwa kwe-electrochemical
  • HVA
  • i-homovanillic acid
  • VMAT2
  • i-neuronal vesicular monoamine transporter
  • VTA
  • indawo yezentlalo

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